Terbium-161 for PSMA-targeted radionuclide therapy of prostate cancer

Abstract

Purpose: The prostate-specific membrane antigen (PSMA) has emerged as an interesting target for radionuclide therapy of metastasized castration-resistant prostate cancer (mCRPC). The aim of this study was to investigate ¹⁶¹Tb (T_1/2 = 6.89 days; Eβ^͞_av = 154 keV) in combination with PSMA-617 as a potentially more effective therapeutic alternative to ¹⁷⁷Lu-PSMA-617, due to the abundant co-emission of conversion and Auger electrons, resulting in an improved absorbed dose profile.

Methods: ¹⁶¹Tb was used for the radiolabeling of PSMA-617 at high specific activities up to 100 MBq/nmol. ¹⁶¹Tb-PSMA-617 was tested in vitro and in tumor-bearing mice to confirm equal properties, as previously determined for ¹⁷⁷Lu-PSMA-617. The effects of ¹⁶¹Tb-PSMA-617 and ¹⁷⁷Lu-PSMA-617 on cell viability (MTT assay) and survival (clonogenic assay) were compared in vitro using PSMA-positive PC-3 PIP tumor cells. ¹⁶¹Tb-PSMA-617 was further investigated in therapy studies using PC-3 PIP tumor-bearing mice.

Results: ¹⁶¹Tb-PSMA-617 and ¹⁷⁷Lu-PSMA-617 displayed equal in-vitro properties and tissue distribution profiles in tumor-bearing mice. The viability and survival of PC-3 PIP tumor cells were more reduced when exposed to ¹⁶¹Tb-PSMA-617 as compared to the effect obtained with the same activities of ¹⁷⁷Lu-PSMA-617 over the whole investigated concentration range. Treatment of mice with ¹⁶¹Tb-PSMA-617 (5.0 MBq/mouse and 10 MBq/mouse, respectively) resulted in an activity-dependent increase of the median survival (36 vs 65 days) compared to untreated control animals (19 days). Therapy studies to compare the effects of ¹⁶¹Tb-PSMA-617 and ¹⁷⁷Lu-PSMA-617 indicated the anticipated superiority of ¹⁶¹Tb over ¹⁷⁷Lu.

Conclusion: ¹⁶¹Tb-PSMA-617 showed superior in-vitro and in-vivo results as compared to ¹⁷⁷Lu-PSMA-617, confirming theoretical dose calculations that indicate an additive therapeutic effect of conversion and Auger electrons in the case of ¹⁶¹Tb. These data warrant more preclinical research for in-depth investigations of the proposed concept, and present a basis for future clinical translation of ¹⁶¹Tb-PSMA-617 for the treatment of mCRPC.

Keywords: 161Tb; Auger electrons; PSMA ligands; Prostate cancer; Radioligand therapy.